The current pandemic of sexually transmitted HIV/AIDS has created an urgent need for a new type of microbicide: one that is both a spermicide and a virucide. In a systematic effort to develop a vaginal microbicidal contraceptive potentially capable of preventing the sexual transmission of I-]]V as well as providing fertility control, we have synthesized a series of novel nonnucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase (RT) with spermicidal activity. Our structure-based drug design by use of a computer docking procedure for the NNI binding pocket generated from nine RT-NNI crystal structures led to the synthesis of a panel of spermicidal NNIs. Our lead compound, N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (PHI-346), was the most potent, non-cytotoxic, dual-function anti-HIV agent against NNI-sensitive, NNI-resistant, and multidrug-resistant strains of HIV-I. The anti-HIV activity of PHI-346 was 700-fold more potent than the currently used detergent-based virucidal spermicide, nonoxyno]-9 (N-9). The spermicidal activity of PHI-346 was 2-fold more potent than that of N-9 and unlike N-9, it was not associated with cytotoxicity to female genital tract epithelial cells. Preclinical studies of a PHI-346 gel formulation given intravaginally, lacked inflammatory and toxic effects in rodent and non-rodent animal models. We hypothesize that PHI-346, because of its broad-spectrum anti-HIV activity, spermicidal efficacy, and lack of inflammatory and toxic effects, may be useful as a dual-function vaginal/rectal microbicide for women who are at high risk of acquiring HIV/AIDS by sexual transmission. The further development of PHI-346 as a dual-function microbicide may provide the foundation for a new strategy to prevent the sexual transmission of multidrug-resistant HIV-1 while providing fertility control for women. The goal of this Phase I proposal is: (i) to evaluate the in vivo anti-HIV efficacy of PHI-346 gel formulation in the vaginal HIV-infected Hu-PBL-SCID mouse model of sexually transmitted AIDS; and (ii) to evaluate the in vivo contraceptive efficacy of PHI-346 gel formulation. Following successful completion of the Phase I in vivo efficacy studies, gel formulation of PHI-346 will be further explored as a vaginal dual-function microbicide in Phase II.